tbuckley/cabot-search huggingface dataset:
Abstract 2926: Structure-based design of quadruplex-binding small molecule compounds: The essential role of water molecules
Authors: Stephen Neidle
Journal: Cancer Research (2022)

Abstract The compounds CM03 and SOP1812 are tri- and tetra-substituted naphthalene diimide derivatives with high affinity for several human DNA quadruplexes. They have been designed by computer modelling based on co-crystal structures of 1st-generation substituted naphthalene diimides with human intramolecular telomeric quadruplexes. CM03 and SOP1812 have single-digit 1-20 nM anti-proliferative activity in a panel of human pancreatic ductal adenocarcinoma (PDAC) cell lines (Marchetti et al., J. Med. Chem, 2018, 61, 2500-2517: Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644) and significant anti-tumor activity in the MIA-PACA2 xenograft model for PDAC as well as in the more demanding KPC model. SOP1812 is bio-available at therapeutic doses and is well tolerated at these levels in animal models. It is currently being evaluated as a candidate for clinical development by Qualigen Therapeutics Inc. The role of water in protein-drug binding is well documented and known to be important for accurate estimates of drug binding energies and for docking/virtual screening studies. To date this factor has not been seriously considered in studies of ligand-quadruplex interactions even though virtual screening has emerged as an important tool for finding new chemotypes and optimizing compound libraries in silico. A high-resolution crystal structure of a naphthalene diimide quadruplex complex (PDB id 3UYH: Micco et al., J. Med. Chem., 2013, 56, 2959-2974) has now been analyzed in detail. Patterns of water molecules have been found in each of the four quadruplex grooves, associated with the cationic side chains. Only a nitrogen atom on each N-methyl-piperazine cationic end groups is in direct hydrogen bonded contact with a phosphate group. The morpholino groups each have a small and well-defined cluster of water molecules mediating between cationic nitrogen atom and phosphate group. The rest of each groove is filled by a second cluster of waters, suggesting that larger substituents can be accommodated. Data from a library of naphthalene diimide derivatives is being examined to validate the role of these waters, especially with respect to their relative mobilities and ease of displacement. Citation Format: Stephen Neidle. Structure-based design of quadruplex-binding small molecule compounds: The essential role of water molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2926.
Abstract 5562: Development of a TERT-specific peptide/adjuvant vaccine in C57BL/6 mice
Authors: Jason D. Marshall, Yurong Song, Hamid Zarkesh, Rebecca L. Matthews, Chelsea Sanders, Simone Difilippantonio, Ligia A. Pinto, Shizuko Sei, Robert H. Shoemaker
Journal: Cancer Research (2022)

Abstract Telomerase plays a vital role in cell senescence and cellular replication and has been described as a leading regulator in several human cancers, including prostate, thyroid, breast, colon, and bladder cancer. Telomerase is responsible for elongating telomere length and prolonging cellular lifespan as well as acting as a transcriptional modulator in cancer signaling pathways. Because of its enhanced expression in primary tumor cells as well as incipient tumor-initiating stem cells and with limited distribution in normal somatic cells, the catalytic component of telomerase, TERT (telomerase reverse transcriptase), is regarded as a high-impact target for immunotherapeutic agents and vaccines. In order to derive a mouse TERT (mTERT)-specific vaccine which could be useful in a preventive approach, we implemented an epitope-mapping stratagem by which pools of 30-mer peptides overlapping by 5 spanning the entire mTERT sequence were used to immunize C57BL/6 mice. Several immunogenic peptides were identified by matrixed peptide pool IFN-ɣ ELISPOT screening in a 2-part process that first identified positive pools, then identified individual peptides. 15-mer and 31-mer versions of the top 7 immunogenic mTERT peptides were synthesized and used as a peptide pool combined separately with several adjuvants to optimize immunogenicity. Results suggested a peptide sequence-specific preference for TLR3-mediated Hiltonol versus TLR9-mediated CpG-based adjuvants. In addition, the majority of T cell responses specific to the TERT peptides was identified through flow cytometry as belonging to the CD4 compartment, although one class I-restricted epitope was also identified. Multifunctional CD4+ T cells expressing IFN-ɣ, TNF-α, IL-2, and CD107a were identified specific to several mTERT peptides. In vivo cytotoxic effects exerted on TERT peptide pool-loaded target cells were also uncovered that were specific to a CpG-adjuvanted version of the vaccine. Finally, multiple versions of the mTERT peptide/adjuvant vaccine with highest immunogenicity scores are being tested in a syngeneic graft mouse model using subcutaneous implantation of lung cancer-derived SPON10 cells expressing mTERT. If proven efficacious, these results will support the feasibility of a TERT peptide/adjuvant approach for prophylactically engendering broad antitumor immunity to TERT-expressing cancers. Funded by NCI Contract No. HHSN261200800001E Citation Format: Jason D. Marshall, Yurong Song, Hamid Zarkesh, Rebecca L. Matthews, Chelsea Sanders, Simone Difilippantonio, Ligia A. Pinto, Shizuko Sei, Robert H. Shoemaker. Development of a TERT-specific peptide/adjuvant vaccine in C57BL/6 mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5562.
Abstract 3023: Fatty acid synthase (FASN) inhibitors synergize with carfilzomib (CFZ) in acute myeloid leukemia (AML) and multiple myeloma (MM)
Authors: Maoyu Peng, Sanaz Noelle Ghafouri, Martina SJ McDermott, Dennis J. Slamon, Sarah M. Larson
Journal: Cancer Research (2022)

Abstract Background: Fatty acid synthase (FASN) upregulation during conditions of oxidative stress contributes to tumor proliferation and survival, which appears to be a mechanism of proteasome inhibitor resistance. Here we demonstrate that acute myeloid leukemia (AML) cell lines resistant to carfilzomib (CFZ), a second-generation proteasome inhibitor, have higher basal FASN expression and targeting FASN with small molecule inhibitors enhances the cytotoxic effect of CFZ in both AML and multiple myeloma (MM) cell lines. Methods: In a proliferation assay, human AML and MM cell lines were treated with a single dose of CFZ for 7 days. Inhibition of proliferation was defined using an IC50 cutoff for CFZ of 10nM for AML and 5nM for MM as the threshold for sensitivity. Sensitive and resistant cell lines were subjected to apoptosis and cell cycle analyses by flow cytometry after being exposed to CFZ for 72 hours. Proteomic analysis was performed at baseline using reverse phase protein assay (RPPA). For CFZ and FASN inhibitor combination assays, AML and MM cell lines with varying sensitivities to CFZ were exposed to CFZ and FASN inhibitors, orlistat or TVB-3166, simultaneously, and the apoptosis rate were analyzed by flow cytometry. For western blots, selected AML and MM cell lines were incubated with compounds for 24 hours, and the lysates were probed for selected targets. Results: Single-agent CFZ induced apoptosis in sensitive AML and MM cell lines, while apoptotic rates remained low in resistant cell lines. Cell cycle analysis showed increased sub-G1 population in sensitive cell lines compared to resistant cell lines. RPPA revealed that FASN, a key enzyme involved in lipogenesis, correlated with CFZ sensitivity, and CFZ resistant lines trended towards higher basal FASN levels. When CFZ was combined with FASN inhibitors, orlistat or TVB-3166, significant synergy was observed in the apoptosis assays in the AML and MM cell lines. Western blot analyses showed FASN inhibitors enhanced the anti-proliferation and pro-apoptotic effects of CFZ. Conclusion: CFZ demonstrated single agent activity in nanomolar ranges in human AML and MM cell lines. When combined with agents targeting lipid-metabolism, CFZ showed synergistic effect in apoptosis, suggesting this combination could potentially be a new therapeutic strategy for AML and MM. Citation Format: Maoyu Peng, Sanaz Noelle Ghafouri, Martina SJ McDermott, Dennis J. Slamon, Sarah M. Larson. Fatty acid synthase (FASN) inhibitors synergize with carfilzomib (CFZ) in acute myeloid leukemia (AML) and multiple myeloma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3023.
Abstract 6265: Do epigenetic outliers impact racial disparities in colorectal cancer
Authors: Jayashri Ghosh, Bryant M. Schultz, Joe Chan, Claudia Wultsch, Imad Shureiqi, Stephanie Chow, Ahmet Doymaz, Sophia Varriano, Melissa Driscoll, Jen Muse, Frida E. Kleiman, Konstantinos Krampis, Jean-Pierre J. Issa, Carmen Sapienza
Journal: Cancer Research (2022)

Abstract African Americans (AA) have a higher incidence and mortality rate for colorectal cancer (CRC) compared to Caucasians. DNA methylation profiling on normal colon mucosa from 77 CRC patients and 68 patients without cancer (controls) of AA and Caucasian descent identified a distinct subgroup of CRC patients (11AA and 4 Caucasians) who are statistical “outliers” at a large number of CpGs. Such highly epigenetically disrupted CRC patients are termed “Outlier Methylation Phenotype” (OMP). Comparison of methylome profiles of CRC patients and controls revealed that AA CRC patients have greater disruption of the normal colon methylome than do Caucasian patients. A large fraction of the overall methylation differences found between CRC patients and controls is attributable to OMPs. Estimation of epigenetic ages shows that OMPs have lower epigenetic ages compared to their chronological ages. In other words, OMPs undergo epigenetic age deceleration. Comparison of normal colon mucosa transcription profiles of OMP cancer patients with those of non-OMP cancer patients indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally down-regulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S RDNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with CRC risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections and KRAS mutations. In conclusion, our study suggests a distinct epigenetically disrupted OMP group in CRC that are responsible for disrupted methylome, altered gene expression and microbial dysbiosis. Furthermore, a higher frequency of OMPs among African Americans (11/42) than among Caucasians (5/35) may contribute to observed racial disparities in CRC incidence and outcome. Citation Format: Jayashri Ghosh, Bryant M. Schultz, Joe Chan, Claudia Wultsch, Imad Shureiqi, Stephanie Chow, Ahmet Doymaz, Sophia Varriano, Melissa Driscoll, Jen Muse, Frida E. Kleiman, Konstantinos Krampis, Jean-Pierre J. Issa, Carmen Sapienza. Do epigenetic outliers impact racial disparities in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6265.
Abstract 1884: Optical coherence tomography for label-free real 3D imaging of <i>ex-vivo</i> tumor cultures
Authors: Maria Mitsi, Riccardo Urbane, Benjamin Simon, Yasushi Kuromi, Ryo Hasebe, Sumeer Dhar
Journal: Cancer Research (2022)

Abstract The use of advanced ex-vivo human organotypic cultures is rapidly growing in the field of oncology research and diagnostics, with a focus on patient-derived organoids and tumor tissue specimens cultured in artificial systems capable of replicating tumor development mechanisms. These mechanisms include metastasis, angiogenesis and formation of dysplasia. Our objective is to enhance the label-free imaging and analytical capabilities of these complex tissue samples to enable screening and diagnostics applications.SCREEN Holdings Inc., has developed a unique infrared laser-based optical coherence tomography (OCT) technology enabling non-invasive, label-free, three-dimensional (3D) imaging of tumoroids, epithelial cystic organoids, sprouting endothelial neo-vasculature and metastatic single cells. The imaging is carried out on the 3DProSeed hydrogel plates developed by Ectica Technologies, a glass-bottom 96-well plate featuring pre-casted, synthetic and optically clear hydrogels for ex-vivo tumor cultures.Here we present culture and imaging protocols with the resulting 3D tomographic reconstructions of endothelial sprouting vessels, cystic epithelial organoids of the colon and 3D invasion assays of highly metastatic glioma cells. Citation Format: Maria Mitsi, Riccardo Urbane, Benjamin Simon, Yasushi Kuromi, Ryo Hasebe, Sumeer Dhar. Optical coherence tomography for label-free real 3D imaging of ex-vivo tumor cultures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1884.
Abstract 2108: ScRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic tumor liver metastasis
Authors: Jie Wang, Qijun Yi, Tingting Liu, Yi Yao, Ian Loveless, Kalpana Subedi, Indra Adrianto, Howard Crawford, Li Zhou, Qing-Sheng Mi
Journal: Cancer Research (2022)

Abstract Background: Liver metastasis is a common feature of pancreatic tumor and associated with a poor outcome. Invariant natural killer cells (iNKT) are innate-like T cells that are important regulators of innate and adaptive immune responses in cancer and is the largest subset of lymphocytes within liver. However, the role of iNKT cells in pancreatic tumor liver metastasis (PTLM) is still not clear. Hypothesis: activated liver iNKT cells could play a role in PTLM. Method: We established a PTLM mouse model by hemi-spleen murine pancreatic tumor cells (CF1242) injection. We combined single-cell RNA sequencing, flow cytometry analysis, and imaging mass cytometry analysis to landscape the immune profile of tumor microenvironment during PTLM with or without iNKT cell activator α-galactosylceramide (αGC) treatment. Results: αGC treatment significantly blocked PTLM development based on liver weight compared to control group(P&amp;lt;0.001). We sequenced total 6,728 CD45+ infiltrating immune cells in PTLM with/without αGC treatment and identified total 12 immune subpopulations that were present in both samples at different frequencies. Post αGC treatment, activated iNKT cells in liver appeared robust population expansion and enriched in cytotoxic signaling pathway. Alternatively, activated iNKT cells promoted infiltrating CD4 T cells to a Th1 profile shift, and promoted infiltrating CD8 T cells toward an effector/memory phenotype (upregulation of the CD44, T-bet, and IFN-γ; P&amp;lt;0.001), and increased NK cell cytotoxic activity (P&amp;lt;0.001). In addition, we observed that aGC treatment blocked infiltrating CD8 T cell exhaustion by downregulating the immune checkpoint TIGIT, Lag3, and PD-1 (P&amp;lt;0.001). Analysis of tumor-infiltrating myeloid clusters revealed that macrophage skewed to M1 phenotype compared to the control group(P&amp;lt;0.05). Conclusion: αGC treatment can expand and activate liver iNKT cells, which may directly increase tumor cell killing ability, recruit immune cells to tumor sites, and orchestrate the anti-tumor function through boost both innate and adaptive tumor immunity to inhibit PTLM. Our results indicate that iNKT cells may serve as a new immunotherapeutic target for PTLM. (Funded by HFCI and NIH/NIAID) Citation Format: Jie Wang, Qijun Yi, Tingting Liu, Yi Yao, Ian Loveless, Kalpana Subedi, Indra Adrianto, Howard Crawford, Li Zhou, Qing-Sheng Mi. ScRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic tumor liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2108.
Abstract 4053: NGY-B is a novel inhibitor of MCT transporters blocking lactate and glucose metabolisms
Authors: Sambad Sharma, Gregory Goreczny, Nicole Bowman, Jennifer Duffy, Daliya Banerjee, Sanath Wijerathna, John Dzuris, Jaime Escobedo, Vincent Sandanayaka
Journal: Cancer Research (2022)

Abstract Aberrant glycolytic flux and mitochondrial respiration are known to drive tumor progression and metastasis. Therefore, targeting metabolic alterations in cancer is critical for developing novel cancer therapeutics. We have developed NGY-B as a first-in-Class small molecule inhibitor of the lactate transporters, MCT1 and MCT4, that also decreases mitochondrial respiration. These transporters play a crucial role in regulating both glycolysis and oxidative phosphorylation in cancer cells. NGY-B treatment exhibited potent in vitro cytotoxicity in cancer cells with various levels of MCT1 and MCT4 expression. The on-target activity of NGY-B was validated by measuring intracellular and extracellular lactate levels. NGY-B blocks lactate import through MCT1 under high lactate conditions and lactate export through MCT4 in high glucose conditions. Seahorse and U-13C-glucose tracing analysis demonstrated NGY-B treatment modulates glycolysis and oxidative phosphorylation consistent with the lactate measurement data. Therefore, NGY-B is a novel inhibitor of MCT1/4 while also exhibiting inhibition of mitochondrial respiration. Citation Format: Sambad Sharma, Gregory Goreczny, Nicole Bowman, Jennifer Duffy, Daliya Banerjee, Sanath Wijerathna, John Dzuris, Jaime Escobedo, Vincent Sandanayaka. NGY-B is a novel inhibitor of MCT transporters blocking lactate and glucose metabolisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4053.
Abstract 5868: Factors associated with exercise participation in patients with breast cancer
Authors: Paulina S. Marell, Janet E. Olson, Joerg Herrmann, Nicole L. Larson, Nathan K. LeBrasseur, Stacy D. D'Andre, Andrea L. Cheville, Toure Barksdale, Charles L. Loprinzi, Fergus J. Couch, Kathryn J. Ruddy
Journal: Cancer Research (2022)

Abstract BACKGROUND: The American Cancer Society recommends at least 150 minutes of moderate and/or strenuous exercise and muscle-strengthening activities each week for adults. Exercise has been associated with decreased breast cancer mortality and adverse symptoms. This study’s purpose is to understand prevalence and predictors of inadequate aerobic exercise in patients recently diagnosed with breast cancer to inform interventions to increase exercise participation. METHODS: Patients seen at least once at Mayo Clinic Rochester were prospectively enrolled within one year of an initial breast cancer diagnosis in the Mayo Clinic Breast Disease Registry after providing informed consent. This analysis includes those who completed a baseline survey with self-reported exercise data using the Godin Leisure-Time Exercise Questionnaire. This longitudinal cohort study was approved by the Mayo Clinic institutional review board. RESULTS: 1,738 participants reported their usual weekly quantity of moderate and strenuous exercise an average of 95 days (SD 71 days, range 0-365) after diagnosis. Table 1 displays participant characteristics overall and by whether participants reported at least 150 minutes of moderate and/or strenuous activity weekly (“met guidelines”) or not (“did not meet guidelines”). Overall, 39% of participants met guidelines, including 56% of those aged 18-39 years, 40% of those aged 40-69 years, and 27% of those aged 70+ years. CONCLUSION: Older age was associated with less likelihood of meeting exercise guidelines (all age groups vs 70+, p &amp;lt; 0.05). A more diverse cohort will be needed to evaluate differences by gender and race/ethnicity. There did not appear to be any obvious impact on exercise level by time since diagnosis (during the first year after diagnosis) or educational status, though substantial missing data limit conclusions related to the latter. Additional research is needed to assess exercise levels later in survivorship and the impact of various treatment modalities on exercise habits Table 1. Patient and tumor characteristics Citation Format: Paulina S. Marell, Janet E. Olson, Joerg Herrmann, Nicole L. Larson, Nathan K. LeBrasseur, Stacy D. D'Andre, Andrea L. Cheville, Toure Barksdale, Charles L. Loprinzi, Fergus J. Couch, Kathryn J. Ruddy. Factors associated with exercise participation in patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5868.
Abstract 2908: PT217, an anti-DLL3/anti-CD47 bispecific antibody, exhibits anti-tumor activity through novel mechanisms of action
Authors: Haiqun(John) Jia, Dorthy Fang, Molly Lobsinger, Yan Long, Kelan Chen, Albert Lam, Yangyang Guo, Kaisa Selesniemi, Ming Wang, Hui Zou
Journal: Cancer Research (2022)

Abstract Small cell lung cancer (SCLC) is the most lethal subtype of lung cancers with few patients surviving more than 5 years from diagnosis. While SCLC initially responds well to standard chemotherapy treatment, chemotherapy-resistant recurrence is characteristic and available treatment options for recurrent and refractory diseases are limited. Immunotherapy as an alternative or additional treatment has been very successful in treating many cancers, yet it has shown disappointingly limited benefits in SCLC and notable treatment related toxicities have been observed. Delta like 3 (DLL3) is an attractive target for SCLC immunotherapy, as its expression is highly restricted to SCLC and can therefore be used for targeting purposes. On the other hand, CD47 is also strongly expressed on the surface of SCLC cells, where it inhibits macrophage-mediated tumor cell killing. We have developed PT217, a DLL3/CD47 bispecific antibody with effector effect competent Fc to specifically target SCLC cells via two mechanisms. First, PT217 blocks the CD47-SIRPα interaction and stimulates phagocytosis of tumor cells by macrophage. Second, PT217 exhibits robust effector effect (ADCC by NK cells and ADPC by macrophage) mediated by the functional Fc of PT217. Interestingly, it appears that the tumor cells targeted by NK cells are subsequently engulfed by macrophage. Elevated phagocytosis of the tumor cells by macrophages and dendritic cells is expected to increase the presentation of tumor neoantigens that may eventually lead to T cell-mediated killing of tumor cells that do not expression DLL3. In vivo, PT217 demonstrated tumor suppression activity in xenograft mouse models. In addition to the strong tumor killing activity, PT217 also demonstrated good safety profile in NHP studies. Furthermore, PT217 exhibits regular mAb-like manufacturability in process development and CMC. We expect to initiate a phase 1 trial to target SCLC in the first half of 2022. Citation Format: Haiqun(John) Jia, Dorthy Fang, Molly Lobsinger, Yan Long, Kelan Chen, Albert Lam, Yangyang Guo, Kaisa Selesniemi, Ming Wang, Hui Zou. PT217, an anti-DLL3/anti-CD47 bispecific antibody, exhibits anti-tumor activity through novel mechanisms of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2908.